Our long term-goal is to investigate novel approaches to prevent HIV transmission by the use of topical microbicides. For this purpose we have developed and implemented a small animal model where human stem cells are used to reconstitute the hematopoietic system of immunodeficient mice (47). In these humanized mice (designated BIT to represent the fact they are generated from a bone marrow transplant of mice previously implanted with a piece of autologous human fetal liver and thymic tissue) there is systemic reconstitution with human hematopoietic cells in all hematopoietic and non-hematopoietic tissues tested. Like non-human primates, these humanized mice are susceptible to infection with X4- or R5-tropic HIV-1 administered either intrarectally or intravaginally (13, 65). Infection results in plasma antigenemia, development of anti-HIV specific human antibodies, and progressive depletion of human CD4+ cells from the peripheral blood. Furthermore, infection can be efficiently prevented by pre-exposure prophylaxis with antivirals (13). In this grant we will use this system to test the hypothesis that topical administration of microbicides can effectively prevent rectal HIV-1 transmission. Specific Aim 1) To determine the potential protective effect of UC781 to prevent rectal HIV-1 infection. Specific Aim 2) To determine the efficacy of topically administered tenofovir (TFV) to prevent rectal HIV-1 transmission. Specific Aim 3) To determine the protective effect of a combination of TFV and UC781 to prevent rectal HIV- 1 transmission